Approximately 80% of patients with melanoma who undergo lymphadenectomy have high-risk features. Of these high risk patients, approximately 30-50% fail locally following surgical resection. Adjuvant radiotherapy after lymphadenectomy for isolated lymph node relapse of melanoma has been used for patients at high risk of further regional relapse. However, the treatment with radiation therapy is not routinely administered due to the systemic failure pattern of the disease, as well as the conception by many that melanoma is a radioresistant malignancy.

The only data available to support the strategy of adjuvant radiation therapy comes from retrospective and Phase II trials. Such trials have typically suffered from poor accrual, limiting the accessibility of the true benefit to radiation therapy. Most recently, the Trans-Tasman Radiation Oncology Group 96.06 Phase II trial examined the utilization of radiotherapy after lymphadenectomy. They demonstrated excellent local control (87% at five years) and a prolonged time to in-field failure following radiotherapy.

Based on that experience, this Intergroup study lead by the Trans-Tasman Radiation Oncology Group reported the results of the first randomized trial designed to assess the effect of RT on the subsequent risk of regional relapse and survival.

Materials and Methods

This multicenter randomized trial assessed patients at high risk of regional relapse based on the number of involved lymph nodes (?1 nodes for parotid, ?2 for cervical or axillary, ?3 for groin), extra nodal spread of tumor, or minimum metastatic node diameter (3 cm for neck or axilla, 4 cm for groin).

For inclusion in this trial, patients had palpable nodal disease and underwent lymphadenectomy with all recurrent disease completely resected. The number of lymph nodes dissected had to be ?25 for parotid and cervical disease, ?10 for axillary disease, and ?6 for groin disease). Patients could not receive other concurrent therapy with radiotherapy.

Eligible patients were randomized to receive radiotherapy or initial observation. Patients in the observation arm could receive radiotherapy for recurrence if they underwent re-resection prior to irradiation.

Radiotherapy was administered within 12 weeks of surgery in 20 fractions to a total dose of 48 Gy over four weeks according to nodal site-specific guidelines for radiation fields and techniques previously reported in prior clinical trials.

The primary endpoint of the study was regional relapse. Secondary endpoints included morbidity, quality of life, patterns of relapse, disease-free survival, and overall survival.

Results

From March 2002 to September 2007, a total of 250 patients from 16 centers were enrolled in the trial. Thirty-three patients were excluded from analysis, most often for the presence of in transit disease (17 patients) or not having palpable disease (12 patients), leaving 217 patients eligible for analysis (109 randomized to radiation therapy, 108 to observation).

The median age of eligible patients was 58 years. Axillary disease was the most common disease site among all patients. Compliance to the radiotherapy protocol, as assessed by an Independent Monitoring Committee, was 79.2%. The main deviations were related to the dose delivered to a reference point and doses exceeding critical structure allowance.

At a median follow-up of 27 months, patients randomized to radiotherapy had a statistically significant improvement in lymph node field control. Regional relapse was observed in 20 patients in the radiotherapy arm and 34 patients in the observation arm (HR 1.77; 95% CI, 1.02–3.08; p = 0.041).

There was no difference in median survival among the two arms (31 months in the radiotherapy arm, 47 months for the observation arm, p = 0.14). There was also no difference in distant or combined distant and local recurrence rates.

Author's Conclusions

In patients with melanoma at high risk for relapse after lymphadenectomy, adjuvant radiotherapy improved regional control.

There was no statistically significant effect on survival with adjuvant radiotherapy.

Radiation therapy was well tolerated with minimal early toxicity.

Radiation therapy should be considered in patients at high risk of disease recurrence following lymphadenectomy.

Clinical/Scientific Implications

This trial represents the first randomized study demonstrating a significant benefit with using radiation therapy after surgery for the treatment of patients with melanoma who are at high risk of lymph node recurrence.

While radiation therapy in the adjuvant or recurrent setting is often not administered, based on retrospective data, the indications most commonly used by practitioners to offer radiotherapy to patients include positive surgical margins or gross residual disease, more than two involved lymph nodes, extranodal disease, or in transit metastasis.

While there has not been a large randomized trial demonstrating a benefit to one fractionation regimen in the adjuvant or recurrent setting, many radiation oncologists in North America treat in 600 cGy twice weekly fractions to 30 Gy, particularly for head and neck melanomas. In vitro data suggests that melanoma cells have a broad shoulder on cell survival curves, indicating a potential benefit to treating with hypofractionation with larger radiation doses per fraction. A greater benefit in local control may have been demonstrated in this study had patients been treated with hypofractionation.

Although no survival benefit was demonstrated in this study, longer follow-up may help to better characterize the impact that adjuvant radiation therapy has on overall survival, local control, and patterns of failure in this patient population. Longer follow-up assessing radiation-induced toxicity, including fibrosis, lymphedema, and brachial plexopathy, are also needed to gage the potential risks of radiation against its benefits in local control. However, it should be noted that local tumor recurrence, which is minimized by radiation therapy, is also associated with patient morbidity.

All patients in this trial had palpable nodal disease, indicating a high disease burden and potential distant occult metastatic disease. This may, in part, have resulted in a lack of survival benefit with radiation therapy. The benefit to radiation therapy may be higher among patients with less extensive disease detected on imaging.

Currently, many patients with larger nodal size, multiple lymph nodes involved, and extranodal disease are currently treated with systemic therapy alone due to lack of prior randomized trials demonstrating a clear benefit in local control or overall survival with the administration of adjuvant therapy.

While this study may not immediately prove to be “practice changing,” practitioners should discuss radiation therapy as a viable option for patients with melanoma who require lymphadenectomy, particularly those at high risk for recurrence.

Future studies could examine earlier integration of radiation therapy, combined modality therapy with radiation therapy and systemic therapy, and better define the criteria to be used to determine if patients should receive adjuvant radiation therapy.